Interpretive Summary: Increased fat cell numbers and low grade inflammation have been associated with development of obesity and metabolic syndrome symptoms such as increased blood glucose and fatty liver disease. A variety of cellular signaling pathways have been associated with these responses to overconsumption of typical “Western diets” high in saturated fats and cholesterol. One possible pathway involves signaling by reactive oxygen radical species generated by a family of enzymes called Nox. In the current study, we compared the responses to long term consumption of a Western diet in wild type mice and mice knocked out for the protein p47phox beginning at weaning. The phox protein is an essential part of the active complex of Nox enzymes 1-3. Wild type mice become fat and developed metabolic syndrome. Knockout males also became fat, but knockout females were completely protected against the development of obesity. Both knockout males and females were resistant to development of elevated glucose and fatty liver. Protection against fatty liver appears to involved reduced fatty acid synthesis in the liver. These data suggest that signaling through reactive oxygen species derived from Nox enzymes plays an important role in development of obesity and metabolic syndrome particularly in females and that Nox pathway may be a new target for anti-obesity drugs and drugs to treat metabolic syndrome.

Technical Abstract:
NADPH oxidase (Nox) enzymes have been implicated in regulation of adipocyte differentiation and inflammation in a variety of tissues. We examined the effects of feeding AIN-93G or a “Western diet” (WD) (45% fat, 0.5% cholesterol) on development of obesity and “metabolic syndrome” in wild type (WT) mice or p47phox -/- mice in which Nox enzymes 1-3 are inactive. Diets were fed between ages 4 and 12 wk. In both male and female WT mice, weight gain, fat pad weight and % adiposity were greater in WD-fed mice compared to AIN-93G (P< 0.05). In p47phox -/- mice, while the males behaved similarly to WT, the females were completely protected against the development of obesity and mean adipocyte size was lower than in WT females fed either diet (P<0.05). WD feeding resulted in hyperglycemia and hepatic triglyceride accumulation in WT, but not knockout mice of either sex (P< 0.05). p47phox -/- had reduced hepatic SREBP-1c and downstream targets: fatty acid synthase and acyl CoA carboxylase mRNAs (P<0.05). These data suggest that signaling through reactive oxygen species derived from Nox enzymes plays an important role in development of obesity and metabolic syndrome particularly in females.